Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis
Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis
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DOI：
10.1002/hipo.20934
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发表时间：
2012-04-01
期刊：
影响因子：
3.5
通讯作者：
Singh, Shashi Bala
中科院分区：
文献类型：
--
作者：
Hota, Kalpana Barhwal;Hota, Sunil Kumar;Singh, Shashi Bala
缺氧和几种神经退行性疾病中的神经元损伤总是与氧化损伤和线粒体功能障碍相关。另一方面，乙酰-L-肉碱（ALCAR）的给药通过不太了解的机制减轻神经元损伤，防止细胞凋亡，并改善缺氧应激中的能量状态。线粒体生物合成可能是ALCAR改善神经元生物能量学的一个可能机制，本研究旨在探讨ALCAR诱导缺氧神经保护的信号通路以及线粒体生物合成的可能发生。为了产生整体缺氧，成年SpragueDawley大鼠暴露于标准温度和湿度条件下的模拟海拔7，620 m。我们在此证明，给予缺氧大鼠ALCAR 2周有效地保护海马神经元免受线粒体功能障碍、兴奋性毒性和神经变性的影响。ALCAR管理导致过氧化物酶体增殖物激活受体？辅激活因子-1a和核呼吸因子-1诱导的线粒体生物合成，其表达受细胞外相关激酶-核因子红细胞2相关因子2（ERK-Nrf 2）介导的机制调节。最值得注意的是，钙缓冲到非功能性线粒体改善兴奋性毒性和改善海马神经元的生物能量状态。总之，这些数据揭示了ALCAR治疗缺血、中风和其他与缺氧应激和兴奋性毒性相关的神经退行性疾病的巨大治疗潜力。(c)2011 Wiley Periodicals，Inc.
Neuronal damage in hypoxia and several neurodegenerative disorders is invariably associated with oxidative damage and mitochondrial dysfunction. Administration of acetyl-L-carnitine (ALCAR) on the other hand attenuates neuronal damage, prevents apoptosis, and improves energy status in hypoxic stress through less understood mechanisms. Becasue mitochondrial biogenesis could be a possible mechanism for ALCAR-induced improvement in bioenergetics in neurons, the present study aimed at exploring signaling pathways of ALCAR-induced neuroprotection in hypoxia and possible occurrence of mitochondrial biogenesis. To create global hypoxia, adult SpragueDawley rats were exposed to a simulated altitude of 7,620 m at standard temperature and humidity conditions. We here demonstrate that administration of ALCAR to hypoxic rats for a period of 2 weeks effectively protected hippocampal neurons from mitochondrial dysfunction, excitotoxicity, and neurodegeneration. ALCAR administration resulted in peroxisome proliferator-activated receptor ? coactivator-1a and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism. Most notably, calcium buffering into nonfunctional mitochondria ameliorated excitotoxicity and improved bioenergetic status of the hippocampal neurons. Together, the data reveal the immense therapeutic potential of ALCAR for the treatment of ischemia, stroke, and other neurodegenerative disorders associated with hypoxic stress and excitotoxicity. (c) 2011 Wiley Periodicals, Inc.